U.S. patent application number 11/814958 was filed with the patent office on 2008-08-14 for hiv inhibiting 2-(4-cyanophenylamino) pyrimidine oxide derivatives.
This patent application is currently assigned to SONY CORPORATION. Invention is credited to Herman Augustinus De Kock, Piet Tom Bert Paul Wigerinck.
Application Number | 20080194602 11/814958 |
Document ID | / |
Family ID | 36570887 |
Filed Date | 2008-08-14 |
United States Patent
Application |
20080194602 |
Kind Code |
A1 |
De Kock; Herman Augustinus ;
et al. |
August 14, 2008 |
Hiv Inhibiting 2-(4-Cyanophenylamino) Pyrimidine Oxide
Derivatives
Abstract
HIV replication inhibitors of formula (I) a pharmaceutically
acceptable addition salt; or a stereochemically isomeric form
thereof, wherein R.sup.1 is halo; R.sup.2 and R.sup.3 each
independently are C.sub.1-6alkyl. Pharmaceutical compositions
containing these compounds as active ingredient and processes for
preparing these compounds and compositions. ##STR00001##
Inventors: |
De Kock; Herman Augustinus;
(Arendonk, BE) ; Wigerinck; Piet Tom Bert Paul;
(Terhagen, BE) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Assignee: |
SONY CORPORATION
MINATO-KU TOKYO
JP
|
Family ID: |
36570887 |
Appl. No.: |
11/814958 |
Filed: |
February 20, 2006 |
PCT Filed: |
February 20, 2006 |
PCT NO: |
PCT/EP06/60115 |
371 Date: |
July 27, 2007 |
Current U.S.
Class: |
514/275 ;
544/297 |
Current CPC
Class: |
C07D 239/48 20130101;
A61P 31/18 20180101 |
Class at
Publication: |
514/275 ;
544/297 |
International
Class: |
C07D 239/48 20060101
C07D239/48; A61K 31/505 20060101 A61K031/505 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 14, 2005 |
DK |
PA 2005-00217 |
Claims
1. A compound of formula ##STR00012## a pharmaceutically acceptable
addition salt; or a stereochemically isomeric form thereof, wherein
R.sup.1 is halo; R.sup.2 and R.sup.3 each independently are
C.sub.1-6alkyl.
2. A compound as claimed in claim 1 wherein R.sup.1 is chloro or
bromo.
3. A compound as claimed in claim 1 wherein R.sup.1 is bromo.
4. A compound as claimed in claim 1 wherein R.sup.2 and R.sup.3 are
methyl.
5. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and as active ingredient a therapeutically
effective amount of a compound as claimed in claim 1.
6. A compound as claimed in claim 1 for use as a medicine.
7. A process for preparing a composition according to claim 5, the
process comprising intimately mixing the active ingredient and the
carrier.
Description
[0001] The present invention is concerned with pyrimidine oxide
derivatives having HIV (Human Immunodeficiency Virus) replication
inhibiting properties, the preparation thereof and pharmaceutical
compositions comprising these compounds.
[0002] Resistance of the HIV virus against currently available HIV
drugs continues to be a major cause of therapy failure. This has
led to the introduction of combination therapy of two or more
anti-HIV agents usually having a different activity profile.
Significant progress was made by the introduction of HAART therapy
(Highly Active Anti-Retroviral Therapy), which has resulted in an
important reduction of morbidity and mortality in HIV patient
populations treated therewith. HAART involves various combinations
of nucleoside reverse transcriptase inhibitors (NRTIs),
non-nucleoside reverse transcriptase inhibitors (NNRTIs) and
protease inhibitors (PIs). Current guidelines for antiretroviral
therapy recommend such triple combination therapy regimen even for
initial treatment. However, these multidrug therapies not always
are effective and never completely eliminate HIV. It has been
reported that half of the patients receiving anti-HIV combination
therapy do not respond fully to the treatment, mainly because of
resistance of the virus to one or more drugs used. Switching to
alternative combinations usually provides temporary relief but any
form of long-term treatment will fail at the end because of the
development of multidrug resistance. Moreover, it has been shown
that resistant virus is carried over to newly infected individuals,
resulting in severely limited therapy options for these drug-naive
patients.
[0003] Therefore, there is a continued need for new drug
combinations that are effective against HIV. New types of HIV
inhibitors, differing in chemical structure and activity profile
are needed in these new combinations. Finding such new active
ingredients therefore is a highly desirable goal to achieve.
[0004] The present invention provides a particular novel series of
bisaryl substituted pyrimidine derivatives which may find use in
HIV therapy, in particular as a new component of drug combinations.
WO-00/27825 describes particular bisaryl substituted pyrimidines
having HIV replication inhibiting properties. The compounds of the
present invention behave superior in terms of HIV replication
inhibiting properties and show improved capability to inhibit the
replication of mutant strains, in particular strains which have
become resistant to one or more known NNRTIs, which strains are
referred to as drug or multidrug resistant HIV strains.
[0005] The present invention concerns compounds of formula
##STR00002##
the pharmaceutically acceptable addition salts; or the
stereochemically isomeric forms thereof, wherein R.sup.1 is halo;
R.sup.2 and R.sup.3 each independently are C.sub.1-6alkyl.
[0006] As used herein the term "C.sub.1-4alkyl" defines straight or
branched chain saturated hydrocarbon radicals having from 1 to 4
carbon atoms such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl,
2-butyl, 2-methyl-1-propyl, and the like; "C.sub.1-6alkyl"
encompasses C.sub.1-4alkyl radicals and the higher homologues
thereof having 5 or 6 carbon atoms such as 1-pentyl, 2-pentyl,
3-pentyl, 1-hexyl, 2-hexyl, 2-methyl-1-butyl, 2-methyl-1-pentyl and
the like. Of interest amongst C.sub.1-6alkyl are the C.sub.1-4alkyl
radicals.
[0007] The term halo encompasses fluoro, chloro, bromo and
iodo.
[0008] The compounds of this invention contain an N-oxide bond
which may be represented by NO, by N.dbd.O, or by N.sup.+--O.sup.-
or, as used mostly in this specification and claims, by
N.fwdarw.O.
[0009] For therapeutic use, salts of the compounds of formula (I)
are those wherein the counter ion is pharmaceutically acceptable.
However, salts which are non-pharmaceutically acceptable may also
find use, for example, in the preparation or purification of a
pharmaceutically acceptable compound. All salts, whether
pharmaceutically acceptable or not are included within the ambit of
the present invention.
[0010] The term "pharmaceutically acceptable addition salts" as
used herein is meant to comprise the therapeutically active
non-toxic acid addition salt forms, which the compounds of formula
(I) are able to form. The latter can conveniently be obtained by
treating the base form with such appropriate acids as inorganic
acids, for example, hydrohalic acids, e.g. hydrochloric,
hydrobromic and the like; sulfuric acid; nitric acid; phosphoric
acid and the like; or organic acids, for example, acetic,
propanoic, hydroxy-acetic, 2-hydroxypropanoic, 2-oxopropanoic,
oxalic, malonic, succinic, maleic, fumaric, malic, tartaric,
2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic,
ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic,
cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and
the like acids. Conversely the salt form can be converted by
treatment with alkali into the free base form. The compounds of
formula (I) containing acidic protons may be converted into their
therapeutically active non-toxic metal or amine addition salt forms
by treatment with appropriate organic and inorganic bases.
[0011] The term addition salt also comprises the hydrates and
solvent addition forms which the compounds of formula (I) are able
to form. Examples of such forms are e.g. hydrates, alcoholates and
the like.
[0012] Some of the compounds of formula (I) and their addition
salts may contain one or more centers of chirality and exist as
stereochemically isomeric forms. Stereoiosomers may exist where
R.sup.2 and R.sup.3 are C.sub.4-6alkyl. The term "stereochemically
isomeric forms" as used herein defines all the possible
stereoisomeric forms which the compounds of formula (I), and their
addition salts may possess. Stereochemically isomeric forms of the
compounds of formula (I) are intended to be embraced within the
scope of this invention.
[0013] Preferred subgroups of compounds is those compounds of
formula (I) as specified above, or any subgroup of compounds of
formula (I) specified herein, wherein R.sup.1 is chloro or bromo,
more preferably wherein R.sup.1 is bromo.
[0014] Other preferred subgroups of compounds is those compounds of
formula (I) as specified above, or any subgroup of compounds of
formula (I) specified herein, wherein R.sup.2 and R.sup.3 are
C.sub.1-4alkyl, more preferably wherein R.sup.2 and R.sup.3 are
C.sub.1-2alkyl, still more preferably wherein R.sup.2 and R.sup.3
are methyl.
[0015] Of particular interest are the compounds of formula (I)
wherein R.sup.1 is bromo and R.sup.2 and R.sup.3 are methyl.
[0016] In general, the compounds of formula (I) can be prepared by
N-oxidizing the corresponding compounds of formula (II) using
art-known procedures for converting a tertiary nitrogen into its
N-oxide form.
##STR00003##
[0017] The N-oxidation reaction to prepare the compounds of formula
(I) may be carried out by reacting the starting material of formula
(II) with an appropriate organic or inorganic peroxide. Appropriate
inorganic peroxides comprise, for example, hydrogen peroxide,
alkali metal or earth alkaline metal peroxides, e.g. sodium
peroxide, potassium peroxide; appropriate organic peroxides may
comprise peroxy acids such as, for example, benzenecarboperoxoic
acid or halo substituted benzenecarboperoxoic acid, e.g.
3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.
peroxoacetic acid, alkylhydroperoxides, e.g. tert.butyl
hydro-peroxide. Preferred is 3-chlorobenzenecarbo-peroxoic acid
(m-CPBA). The N-oxidation reaction usually is conducted in a
suitable solvent such as, for example, water; a lower alcohol, e.g.
ethanol and the like; a hydrocarbon, e.g. toluene; a ketone, e.g.
acetone or 2-butanone; a halogenated hydro-carbon, e.g.
dichloromethane or chlorophorm; and any mixtures of such solvents.
Preferred are halogenated hydrocarbons, in particular
dichloromethane. The end products may be purified using methods
generally known in the art such as extraction, crystallization,
trituration and chromatography.
[0018] The starting compounds of formula (II) are known compounds,
which can be prepared according to procedures described in
WO00/27825. They can be prepared by reacting an intermediate of
formula (III) or (V) with an intermediate of formula (IV) or (VI),
as outlined in the following reaction scheme, wherein R.sup.1,
R.sup.2 and R.sup.3 are as specified for the compounds of formula
(I) or any subgroup thereof and W represents a suitable leaving
group, such as for example halogen, e.g. chloro and the like.
##STR00004##
[0019] The reaction of the pyrimidine derivative (III) respectively
(V) with the cyanoaniline (IV) respectively the cyanophenyl
derivative (VI), is preferably conducted in a suitable solvent,
such as for example an alcohol, such as for example methanol,
ethanol, 2-propanol; N,N-dimethylformamide; N,N-dimethylacetamide,
1-methyl-2-pyrrolidinone; 1,4-dioxane, propylene glycol
monomethylether; acetonitrile. The reactions may be done under
acidic conditions which may be obtained by adding a suitable acid,
e.g. camphor sulfonic acid, to a suitable solvent, such as for
example tetrahydrofuran or an alcohol, e.g. ethanol, 1- or
2-propanol, or by using acidified solvents, e.g. hydrochloric acid
dissolved in an alkanol such as ethanol, 1- or 2-propanol.
[0020] The compounds of formula (II) can also be prepared by
reacting a cyanophenyl derivative (VII) with a pyrimidine
derivative (VIII) or by reacting a cyanophenyl derivative (IX) with
a pyrimidine derivative (X) as outlined in the following
schemes.
##STR00005##
[0021] In these reaction schemes R.sup.1, R.sup.2 and R.sup.3 are
as specified for the compounds of formula (I) or any subgroup
thereof and W represents a suitable leaving group, such as for
example halogen, e.g. chloro and the like. These reactions
preferably are conducted in a suitable solvent, in particular any
of the solvents mentioned above in relation to the reaction of
(III) with (IV).
[0022] Still another way to prepare compounds of formula (II) is by
halogenating a starting material (XI) with free halogen, e.g. free
chlorine or bromine, or with a halogen donor such as N-bromo or
N-chloro succinimide. This halogenation reaction preferably is
conducted in a suitable reaction-inert solvent such as an ether, in
particular in THF. N-bromo or N-chloro succinimide can be used in
the presence of acetic acid.
##STR00006##
[0023] The compounds of formula (I) may further be prepared by
converting compounds of formula (I) into each other according to
art-known group transformation reactions. For example the chloro
analogs can be converted to the corresponding bromo analogs, or
vice versa, by a halogen exchange reaction.
[0024] The compounds of formula (I) can also be prepared using any
of the procedures known or described herein to prepare the
compounds of formula (II) but replacing, where possible, the
pyrimidine starting materials by the corresponding pyrimidine
oxides. The latter can be prepared by a similar N-oxidation
reaction as described for the conversion of (II) into (I).
[0025] Some of the compounds of formula (I) and some of the
precursor intermediates thereof may contain an asymmetric atom.
Pure stereochemically isomeric forms of said compounds and said
intermediates can be obtained by the application of art-known
procedures.
[0026] The synthesis of some intermediates used in the previous
reaction schemes is described hereinafter wherein in the following
reaction schemes R.sup.1, R.sup.2 and R.sup.3 are as specified for
the compounds of formula (I) or any subgroup thereof and W
represents a suitable leaving group, in particular chloro or bromo.
The radical R.sup.1 is halo but in the following reaction schemes
it may also represent a precursor of a halo group such as hydroxy
or a protected hydroxy (e.g. benzyloxy) which can be converted into
a halo group by a halogenating agent such as POCl.sub.3 or
POBr.sub.3. This may be preferred to avoid undesired side
reactions.
[0027] Intermediates of formula (III) can be prepared by reacting a
phenol derivative (XII) with a pyrimidine derivative (XIII) as
outlined in the following reaction scheme.
##STR00007##
[0028] In a similar manner, intermediates (V) can be prepared
starting from a pyrimidine (XV) as outlined in the following
scheme:
##STR00008##
[0029] In the above reaction the amino group may or may not be
protected by a suitable protective group.
[0030] Intermediates (X) can be prepared by condensing a pyrimidine
derivative (XVI) with 4-aminobenzonitrile as outlined in the
following scheme. If desired to avoid side reactions, the --OH
and/or amino group may be protected and R.sup.1 may be a precursor
of halo as set forth above.
##STR00009##
[0031] Intermediates of formula (XI) can be prepared as outlined in
the reaction scheme represented here below. First
4-aminobenzonitrile is reacted with cyanamide to yield
4-cyanophenyl guanidine (XVII). This reaction may be conducted in
water in the presence of a strong acid, e.g. hydrochloric acid, at
increased temperature, e.g. at about 50.degree. C. to 70.degree.
C., e.g. at about 60.degree. C. The latter is reacted with a
diC.sub.1-6alkyl malonic ester of formula (XVIII), wherein each R
independently is C.sub.1-6alkyl, preferably each R is methyl. This
reaction may be conducted in a suitable solvent, e.g. an alcohol
such as methanol, in the presence of a strong base such as an
alkali metal alkoxide, e.g. sodium methoxide, at increased
temperature such as at reflux temperature. The thus obtained
4,6-dihydroxypyrimidine (XIX) is converted to a pyrimidine
derivative (XX) wherein each W is a leaving group and in particular
is halo, preferably chloro or bromo. This conversion can be done by
using a suitable halogenating agent such as POCl.sub.3 or
POBr.sub.3 in a suitable solvent, in particular a polar aprotic
solvent, e.g. in DMF, DMA, HMPT, N-methylpyrrolidone, DMSO and the
like, preferably in acetonitrile. Other leaving groups can be
introduced following art-know alcohol to leaving group conversion
reactions. The pyrimidine derivative (XX) is then reacted with a
4-substituted benzonitrile (XXI) to yield the desired intermediates
(XXI). The reaction of (XX) with (XXI) may be conducted in a
suitable solvent such as an ether, e.g. THF, a halogenated
hydrocarbon, e.g. CH.sub.2Cl.sub.2, CHCl.sub.3 and in particular a
polar aprotic solvent, e.g. in DMF, DMA, HMPT, acetonitrile, DMSO
and the like, and preferably in N-methyl-pyrrolidone. A base may be
added to pick up the acid that is liberated during the course of
the reaction, e.g. an alkali metal carbonate such as potassium
carbonate.
##STR00010##
[0032] The compounds of formula (I) show antiretroviral properties
(reverse transcriptase inhibiting properties), in particular they
are active against HIV, which is the aetiological agent of Acquired
Immune Deficiency Syndrome (AIDS) in humans. HIV preferentially
infects human T-4 cells and destroys them or changes their normal
function, particularly the coordination of the immune system. As a
result, an infected patient has an ever-decreasing number of T-4
cells, which moreover behave abnormally. Hence, the immunological
defense system is unable to combat infections and neoplasms and the
HIV infected subject usually dies by opportunistic infections such
as pneumonia, or by cancers. Other conditions associated with HIV
infection include thrombocytopaenia, Kaposi's sarcoma and infection
of the central nervous system characterized by progressive
demyelination, resulting in dementia and symptoms such as,
progressive dysarthria, ataxia and disorientation. HIV infection
further has also been associated with peripheral neuropathy,
progressive generalized lymphadenopathy (PGL) and AIDS-related
complex (ARC).
[0033] The present compounds also show activity against mutated HIV
strains, including as well single, double, triple or multiple
mutated strains. The compounds of this invention are active against
(multi) drug resistant HIV strains, in particular (multi) drug
resistant HIV-1 strains, more in particular the present compounds
show activity against HIV strains, especially HIV-1 strains that
have acquired resistance to one or more art-known non-nucleoside
reverse transcriptase inhibitors. Art-known non-nucleoside reverse
transcriptase inhibitors are those non-nucleoside reverse
transcriptase inhibitors other than the present compounds and known
to the person skilled in the art, in particular commercial
non-nucleoside reverse transcriptase inhibitors. The present
compounds may have little or no binding affinity to human .alpha.-1
acid glycoprotein; human .alpha.-1 acid glycoprotein may not or
only weakly affect the anti HIV activity of the present
compounds.
[0034] Due to their antiretroviral properties, in particular their
anti-HIV properties, especially their anti-HIV-1-activity, the
compounds of formula (I), the pharmaceutically acceptable addition
salts and stereochemically isomeric forms thereof, are useful in
the treatment of individuals infected by HIV and for the
prophylaxis of these infections. In general, the compounds of the
present invention may be useful in the treatment of warm-blooded
animals infected with viruses whose existence is mediated by, or
depends upon, the enzyme reverse transcriptase. Conditions which
may be prevented or treated with the compounds of the present
invention, especially conditions associated with HIV and other
pathogenic retroviruses, include AIDS, AIDS-related complex (ARC),
progressive generalized lymphadenopathy (PGL), as well as chronic
Central Nervous System diseases caused by retroviruses, such as,
for example HIV mediated dementia and multiple sclerosis.
[0035] The compounds of the present invention or any subgroup
thereof may therefore be used as medicines against above-mentioned
conditions. Said use as a medicine or method of treatment comprises
the administration to HIV-infected subjects of an amount effective
to combat the conditions associated with HIV and other pathogenic
retroviruses, especially HIV-1. In particular, the compounds of
formula (I) may be used in the manufacture of a medicament for the
treatment or the prevention of HIV infections.
[0036] In a further aspect of this invention, there is provided a
method of treating warm-blooded animals, including humans,
suffering from, or a method of preventing warm-blooded animals,
including humans, to suffer from viral infections, especially HIV
infections. Said method comprises the administration, preferably
oral administration, of an effective amount of a compound of
formula (I), a pharmaceutically acceptable addition salt or a
possible stereoisomeric form thereof, to warm-blooded animals,
including humans.
[0037] In another aspect, the compounds of formula (I) or any
subgroup thereof are useful in a method for preventing, treating or
combating infection or disease associated with infection of a
mammal with a mutant HIV virus, comprising administering to said
mammal an effective amount of a compound of formula (I) or any
subgroup thereof.
[0038] In another aspect, the compounds of formula (I) or any
subgroup thereof are useful in a method for preventing, treating or
combating infection or disease associated with infection of a
mammal with a multi drug-resistant HIV virus, comprising
administering to said mammal an effective amount of a compound of
formula (I) or any subgroup thereof.
[0039] In yet another aspect, the compounds of formula (I) or any
subgroup thereof are useful in a method for inhibiting replication
of a HIV virus, in particular a HIV virus having a mutant HIV
reverse transcriptase, more in particular a multi-drug resistant
mutant HIV reverse transcriptase, comprising administering to a
mammal in need thereof an effective amount of a compound of formula
(I) or any subgroup thereof.
[0040] Preferably, a mammal as mentioned in the methods of this
invention is a human being.
[0041] The present invention also provides compositions for
treating viral infections comprising a therapeutically effective
amount of a compound of formula (I) and a pharmaceutically
acceptable carrier or diluent.
[0042] The compounds of the present invention or any subgroup
thereof may be formulated into various pharmaceutical forms for
administration purposes. As appropriate compositions there may be
cited all compositions usually employed for systemically
administering drugs. To prepare the pharmaceutical compositions of
this invention, an effective amount of the particular compound,
optionally in addition salt form, as the active ingredient is
combined in intimate admixture with a pharmaceutically acceptable
carrier, which carrier may take a wide variety of forms depending
on the form of preparation desired for administration. These
pharmaceutical compositions are desirable in unitary dosage form
suitable, particularly, for administration orally, rectally,
percutaneously, or by parenteral injection. For example, in
preparing the compositions in oral dosage form, any of the usual
pharmaceutical media may be employed such as, for example, water,
glycols, oils, alcohols and the like in the case of oral liquid
preparations such as suspensions, syrups, elixirs, emulsions and
solutions; or solid carriers such as starches, sugars, kaolin,
diluents, lubricants, binders, disintegrating agents and the like
in the case of powders, pills, capsules, and tablets. Because of
their ease in administration, tablets and capsules represent the
most advantageous oral dosage unit forms, in which case solid
pharmaceutical carriers are obviously employed. For parenteral
compositions, the carrier will usually comprise sterile water, at
least in large part, though other ingredients, for example, to aid
solubility, may be included. Injectable solutions, for example, may
be prepared in which the carrier comprises saline solution, glucose
solution or a mixture of saline and glucose solution. Injectable
suspensions may also be prepared in which case appropriate liquid
carriers, suspending agents and the like may be employed. Also
included are solid form preparations, which are intended to be
converted, shortly before use, to liquid form preparations. In the
compositions suitable for percutaneous administration, the carrier
optionally comprises a penetration enhancing agent and/or a
suitable wetting agent, optionally combined with suitable additives
of any nature in minor proportions, which additives do not
introduce a significant deleterious effect on the skin. Said
additives may facilitate the administration to the skin and/or may
be helpful for preparing the desired compositions. These
compositions may be administered in various ways, e.g., as a
transdermal patch, as a spot-on, as an ointment. The compounds of
the present invention may also be administered via inhalation or
insufflation by means of methods and formulations employed in the
art for administration via this way. Thus, in general the compounds
of the present invention may be administered to the lungs in the
form of a solution, a suspension or a dry powder. Any system
developed for the delivery of solutions, suspensions or dry powders
via oral or nasal inhalation or insufflation are suitable for the
administration of the present compounds.
[0043] To aid solubility of the compounds of formula (I), suitable
ingredients, e.g. cyclo-dextrins, may be included in the
compositions. Appropriate cyclodextrins are .alpha.-, .beta.-,
.gamma.-cyclodextrins or ethers and mixed ethers thereof wherein
one or more of the hydroxy groups of the anhydroglucose units of
the cyclodextrin are substituted with C.sub.1-6alkyl, particularly
methyl, ethyl or isopropyl, e.g. randomly methylated .beta.-CD;
hydroxy-C.sub.1-6alkyl, particularly hydroxyethyl, hydroxy-propyl
or hydroxybutyl; carboxy-C.sub.1-6alkyl, particularly carboxymethyl
or carboxy-ethyl; C.sub.1-6alkylcarbonyl, particularly acetyl.
Especially noteworthy as complexants and/or solubilizers are
.beta.-CD, randomly methylated 1-CD, 2,6-dimethyl-.beta.-CD,
2-hydroxyethyl-.beta.-CD, 2-hydroxyethyl-.beta.-CD,
2-hydroxypropyl-.beta.-CD and (2-carboxymethoxy)propyl-.beta.-CD,
and in particular 2-hydroxypropyl-.beta.-CD (2-HP-.beta.-CD).
Another type of substituted cyclodextrins is
sulfobutylcyclodextrines.
[0044] The term mixed ether denotes cyclodextrin derivatives
wherein at least two cyclo-dextrin hydroxy groups are etherified
with different groups such as, for example, hydroxy-propyl and
hydroxyethyl.
[0045] The average molar substitution (M.S.) is used as a measure
of the average number of moles of alkoxy units per mole of
anhydroglucose. The average substitution degree (D.S.) refers to
the average number of substituted hydroxyls per anhydroglucose
unit. The M.S, and D.S. value can be determined by various
analytical techniques such as nuclear magnetic resonance (NMR),
mass spectrometry (MS) and infrared spectroscopy (IR). Depending on
the technique used, slightly different values may be obtained for
one given cyclodextrin derivative. Preferably, as measured by mass
spectrometry, the M.S. ranges from 0.125 to 10 and the D.S. ranges
from 0.125 to 3.
[0046] Other suitable compositions for oral or rectal
administration comprise particles consisting of a solid dispersion
comprising a compound of formula (I) and one or more appropriate
pharmaceutically acceptable water-soluble polymers.
[0047] The term "solid dispersion" used hereinafter defines a
system in a solid state (as opposed to a liquid or gaseous state)
comprising at least two components, in case the compound of formula
(I) and the water-soluble polymer, wherein one component is
dispersed more or less evenly throughout the other component or
components (in case additional pharmaceutically acceptable
formulating agents, generally known in the art, are included, such
as plasticizers, preservatives and the like). When said dispersion
of the components is such that the system is chemically and
physically uniform or homogenous throughout or consists of one
phase as defined in thermo-dynamics, such a solid dispersion will
be called "a solid solution". Solid solutions are preferred
physical systems because the components therein are usually readily
bioavailable to the organisms to which they are administered.
[0048] The term "solid dispersion" also comprises dispersions,
which are less homogenous throughout than solid solutions. Such
dispersions are not chemically and physically uniform throughout or
comprise more than one phase, for example, systems having domains
or small regions wherein amorphous, microcrystalline or crystalline
compound of formula (I), or amorphous, microcrystalline or
crystalline water-soluble polymer, or both, are dispersed more or
less evenly in another phase comprising water-soluble polymer, or
compound of formula (I), or a solid solution comprising compound of
formula (I) and water-soluble polymer. Said domains are regions
within the solid dispersion distinctively marked by some physical
feature, small in size, and evenly and randomly distributed
throughout the solid dispersion.
[0049] Various techniques exist for preparing solid dispersions
including melt-extrusion, spray-drying and solution-evaporation.
After preparing the solid dispersions, the obtained products can be
optionally milled and sieved. The solid dispersion product may be
milled or ground to particles having a particle size of less than
600 .mu.m, preferably less than 400 .mu.m and most preferably less
than 125 .mu.m. The particles prepared as described hereinabove can
then be formulated by conventional techniques into pharmaceutical
dosage forms such as tablets and capsules.
[0050] The water-soluble polymers in the particles are polymers
that have an apparent viscosity, when dissolved at 20.degree. C. in
an aqueous solution at 2% (w/v), of 1 to 5000 mPas more preferably
of 1 to 700 mPas, and most preferred of 1 to 100 mPas. For example,
suitable water-soluble polymers include alkylcelluloses,
hydroxyalkyl-celluloses, hydroxyalkyl alkylcelluloses,
carboxyalkylcelluloses, alkali metal salts of
carboxyalkylcelluloses, carboxyalkylalkylcelluloses,
carboxyalkylcellulose esters, starches, pectines, chitin derivates,
di-, oligo- and polysaccharides such as trehalose, alginic acid or
alkali metal and ammonium salts thereof, carrageenans,
galactomannans, tragacanth, agar-agar, gum arabic, guar gum and
xanthan gum, polyacrylic acids and the salts thereof,
polymethacrylic acids and the salts thereof, methacrylate
copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of
polyvinylpyrrolidone with vinyl acetate, combinations of
polyvinylalcohol and polyvinylpyrrolidone, polyalkylene oxides and
copolymers of ethylene oxide and propylene oxide. Preferred
water-soluble polymers are hydroxypropyl methylcelluloses.
[0051] Also one or more cyclodextrins can be used as water-soluble
polymer in the preparation of the above-mentioned particles as is
disclosed in WO 97/18839. Said cyclodextrins include the
pharmaceutically acceptable unsubstituted and substituted
cyclodextrins known in the art, more particularly .alpha., .beta.
or .gamma. cyclodextrins or the pharmaceutically acceptable
derivatives thereof.
[0052] Substituted cyclodextrins which can be used to prepare the
above described particles include polyethers described in U.S. Pat.
No. 3,459,731. Further substituted cyclodextrins are those
described above as agents to aid solubility of the compounds of
formula (I).
[0053] The ratio of the compound of formula (I) over the
water-soluble polymer may vary widely. For example ratios of 1/100
to 100/1 may be applied. Interesting ratios of the compound of
formula (I) over cyclodextrin range from about 1/10 to 10/1. More
interesting ratios range from about 1/5 to 5/1.
[0054] It may further be convenient to formulate the compounds of
formula (I) in the form of nanoparticles which have a surface
modifier adsorbed on the surface thereof in an amount sufficient to
maintain an effective average particle size of less than 1000 nm.
Useful surface modifiers are believed to include those which
physically adhere to the surface of the compound of formula (I) but
do not chemically bind to said compound and may be selected from
known organic and inorganic pharmaceutical excipients. Such
excipients include various polymers, low molecular weight
oligomers, natural products and surfactants. Preferred surface
modifiers include nonionic and anionic surfactants.
[0055] Yet another interesting way of formulating the compounds of
formula (I) involves a pharmaceutical composition whereby the
compounds of formula (I) are incorporated in hydrophilic polymers
and applying this mixture as a coat film over many small beads,
thus yielding a composition which can conveniently be manufactured
and which is suitable for preparing pharmaceutical dosage forms for
oral administration. Such beads comprise a central, rounded or
spherical core, a coating film of a hydrophilic polymer and a
compound of formula (I) and optionally a seal-coating layer.
Materials suitable for use as cores in the beads are manifold,
provided that said materials are pharmaceutically acceptable and
have appropriate dimensions and firmness. Examples of such
materials are polymers, inorganic substances, organic substances,
and saccharides and derivatives thereof.
[0056] It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in unit dosage form for
ease of administration and uniformity of dosage. Unit dosage form
as used herein refers to physically discrete units suitable as
unitary dosages, each unit containing a predetermined quantity of
active ingredient calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier.
Examples of such unit dosage forms are tablets (including scored or
coated tablets), capsules, pills, powder packets, wafers,
suppositories, injectable solutions or suspensions and the like,
and segregated multiples thereof.
[0057] Those of skill in the treatment of HIV-infection could
determine the effective daily amount from the test results
presented here. In general it is contemplated that an effective
daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more
preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be
appropriate to administer the required dose as two, three, four or
more sub-doses at appropriate intervals throughout the day. Said
sub-doses may be formulated as unit dosage forms, for example,
containing 1 to 1000 mg, and in particular 5 to 200 mg of active
ingredient per unit dosage form.
[0058] The exact dosage and frequency of administration depends on
the particular compound of formula (I) used, the particular
condition being treated, the severity of the condition being
treated, the age, weight and general physical condition of the
particular patient as well as other medication the individual may
be taking, as is well known to those skilled in the art.
Furthermore, it is evident that said effective daily amount may be
lowered or increased depending on the response of the treated
subject and/or depending on the evaluation of the physician
prescribing the compounds of the instant invention. The effective
daily amount ranges mentioned hereinabove are therefore only
guidelines and are not intended to limit the scope or use of the
invention to any extent.
[0059] The present compounds of formula (I) can be used alone or in
combination with other therapeutic agents, such as anti-virals,
antibiotics, immunomodulators or vaccines for the treatment of
viral infections. They may also be used alone or in combination
with other prophylactic agents for the prevention of viral
infections. The present compounds may be used in vaccines and
methods for protecting individuals against viral infections over an
extended period of time. The compounds may be employed in such
vaccines either alone or together with other compounds of this
invention or together with other anti-viral agents in a manner
consistent with the conventional utilization of reverse
transcriptase inhibitors in vaccines. Thus, the present compounds
may be combined with pharmaceutically acceptable adjuvants
conventionally employed in vaccines and administered in
prophylactically effective amounts to protect individuals over an
extended period of time against HIV infection.
[0060] Also, the combination of one or more additional
antiretroviral compounds and a compound of formula (I) can be used
as a medicine. Thus, the present invention also relates to a
product containing (a) a compound of formula (I), and (b) one or
more additional antiretroviral compounds, as a combined preparation
for simultaneous, separate or sequential use in anti-HIV treatment.
The different drugs may be combined in a single preparation
together with pharmaceutically acceptable carriers. Said other
antiretroviral compounds may be any known antiretroviral compounds
such as suramine, pentamidine, thymopentin, castanospermine,
dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono
formate); nucleoside reverse transcriptase inhibitors (NRTIs), e.g.
zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine
(3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), D-D4FC
(Reverset.TM.), alovudine (MIV-310), amdoxovir (DAPD), elvucitabine
(ACH-126,443), and the like; non-nucleoside reverse transcriptase
inhibitors (NNRTIs) such as delarvidine (DLV), efavirenz (EFV),
nevirapine (NVP), capravirine (CPV), calanolide A, TMC120,
etravirine (TMC125), TMC278, BMS-561390, DPC-083 and the like;
nucleotide reverse transcriptase inhibitors (NtRTIs), e.g.
tenofovir (TDF) and tenofovir disoproxil fumarate, and the like;
compounds of the TIBO
(tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and
thione)-type e.g.
(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4-
,5,1-jk][1,4]benzodiazepine-2(1H)-thione; compounds of the
.alpha.-APA (.alpha.-anilino phenyl acetamide) type e.g.
.alpha.-[(2-nitrophenyl)amino]-2,6-dichlorobenzene-acetamide and
the like; inhibitors of trans-activating proteins, such as
TAT-inhibitors, e.g. RO-5-3335; REV inhibitors; protease inhibitors
e.g. ritonavir (RTV), saquinavir (SQV), lopinavir (ABT-378 or LPV),
indinavir (IDV), amprenavir (VX-478), TMC-126, BMS-232632, VX-175,
DMP-323, DMP-450 (Mozenavir), nelfinavir (AG-1343), atazanavir (BMS
232,632), palinavir, TMC-114, RO033-4649, fosamprenavir (GW433908
or VX-175), P-1946, BMS 186,318, SC-55389a, L-756,423, tipranavir
(PNU-140690), BILA 1096 BS, U-140690, and the like; entry
inhibitors which comprise fusion inhibitors (e.g. T-20, T-1249),
attachment inhibitors and co-receptor inhibitors; the latter
comprise the CCR5 antagonists and CXR4 antagonists (e.g. AMD-3100);
examples of entry inhibitors are enfuvirtide (ENF), GSK-873,140,
PRO-542, SCH-417,690, TNX-355, maraviroc (UK-427,857); a maturation
inhibitor for example is PA-457 (Panacos Pharmaceuticals);
inhibitors of the viral integrase; ribonucleotide reductase
inhibitors (cellular inhibitors), e.g. hydroxyurea and the
like.
[0061] By administering the compounds of the present invention with
other anti-viral agents, which target different events in the viral
life cycle, the therapeutic effect of these compounds can be
potentiated. Combination therapies as described above exert a
synergistic effect in inhibiting HIV replication because each
component of the combination acts on a different site of HIV
replication. The use of such combinations may reduce the dosage of
a given conventional anti-retroviral agent which would be required
for a desired therapeutic or prophylactic effect as compared to
when that agent is administered as a monotherapy. These
combinations may reduce or eliminate the side effects of
conventional single anti-retroviral therapy while not interfering
with the anti-viral activity of the agents. These combinations
reduce potential of resistance to single agent therapies, while
minimizing any associated toxicity. These combinations may also
increase the efficacy of the conventional agent without increasing
the associated toxicity.
[0062] The compounds of the present invention may also be
administered in combination with immunomodulating agents, e.g.
levamisole, bropirimine, anti-human alpha interferon antibody,
interferon alpha, interleukin 2, methionine enkephalin,
diethyldithio-carbamate, tumor necrosis factor, naltrexone and the
like; antibiotics, e.g. pentamidine isethiorate and the like;
cholinergic agents, e.g. tacrine, rivastigmine, donepezil,
galantamine and the like; NMDA channel blockers, e.g. memantine to
prevent or combat infection and diseases or symptoms of diseases
associated with HIV infections, such as AIDS and ARC, e.g.
dementia. A compound of formula (I) can also be combined with
another compound of formula (I).
[0063] Although the present invention focuses on the use of the
present compounds for preventing or treating HIV infections, the
present compounds may also be used as inhibitory agents for other
viruses, which depend on similar reverse transcriptases for their
reproduction.
[0064] The following examples are intended to illustrate the
present invention and not to limit its scope thereto.
EXAMPLES
Example 1
Synthesis of
4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimet-
hylbenzonitrile
##STR00011##
[0066] A mixture of
4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimet-
hylbenzonitrile (Intermediate 1; 5.00 g, 11.5 mmol) and m-CPBA (3
equiv., 34.5 mmol, 8.50 g 70 wt %) was refluxed in dichloromethane
(100 ml). After 10 minutes a clear solution was formed and 5
minutes later a precipitate formed. The mixture was refluxed for an
additional 15 minutes, cooled to room temperature and the white
solid was filtered and rinsed with dichloromethane. The solid was
stirred in acetic acid for 1 hour, filtered and dried to give 1.7 g
(33%) of Compound 1.
[0067] Physical data: mp. 271.degree. C. (AcOH),
[0068] .sup.1H NMR (300 MHz, DMSO) .delta. 1.90 (s, 2.25H, AcOH),
2.12 (s, 6H), 7.39 (d, 2H), 7.40 (d, 2H), 7.76 (s, 2H), 7.95 (br s,
2H), 10.2 (br s, 1H). The product contains 0.75 equivalents of
acetic acid.
[0069] LCMS analysis (1 ml/min linear gradient to 95% 10 mM aqueous
HCOOH/acetonitrile to t.sub.15 5% 10 mM aqueous HCOOH/acetonitrile,
UV-DAD): 95% pure, t=9.49 min, mass spectrum m/z 449, 451
[M-H].sup.-.
Example 2
Formulations
Capsules
[0070] Compound 1 as described in example 1, is dissolved in
organic solvent such as ethanol, methanol or methylene chloride,
preferably, a mixture of ethanol and methylene chloride. Polymers
such as polyvinylpyrrolidone copolymer with vinyl acetate (PVP-VA)
or hydroxypropylmethylcellulose (HPMC), typically 5 mPas, are
dissolved in organic solvents such as ethanol, methanol methylene
chloride. Suitably the polymer is dissolved in ethanol. The polymer
and compound solutions are mixed and subsequently spray dried. The
ratio of compound/polymer is selected from 1/1 to 1/6. Intermediate
ranges can be 1/1.5 and 1/3. A suitable ratio can be 1/6. The
spray-dried powder, a solid dispersion, is subsequently filled in
capsules for administration. The drug load in one capsule ranges
between 50 and 100 mg depending on the capsule size used.
Film-Coated Tablets
Preparation of Tablet Core
[0071] A mixture of 100 g of a compound 1, 570 g lactose and 200 g
starch are mixed well and thereafter humidified with a solution of
5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about
200 ml of water. The wet powder mixture is sieved, dried and sieved
again. Then there is added 100 g microcrystalline cellulose and 15
g hydrogenated vegetable oil. The whole is mixed well and
compressed into tablets, giving 10.000 tablets, each comprising 10
mg of the active ingredient.
Coating
[0072] To a solution of 10 g methylcellulose in 75 ml of
denaturated ethanol there is added a solution of 5 g of
ethylcellulose in 150 ml of dichloromethane. Then there is added 75
ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of
polyethylene glycol is molten and dissolved in 75 ml of
dichloromethane. The latter solution is added to the former and
then there is added 2.5 g of magnesium octadecanoate, 5 g of
polyvinyl-pyrrolidone and 30 ml of concentrated color suspension
and the whole is homogenated. The tablet cores are coated with the
thus obtained mixture in a coating apparatus.
Example 3
Antiviral Spectrum
[0073] Because of the increasing emergence of drug resistant HIV
strains, the present compounds were tested for their potency
against clinically isolated HIV strains harboring several
mutations. These mutations are associated with resistance to
reverse transcriptase inhibitors and result in viruses that show
various degrees of phenotypic cross-resistance to the currently
commercially available drugs such as for instance AZT and
delavirdine.
[0074] The antiviral activity of the compound of the present
invention is evaluated in the presence of wild type HIV and HIV
mutants bearing mutations at the reverse transcriptase gene. The
activity of the compounds is evaluated using a cellular assay and
the residual activity is expressed in pEC.sub.50 values. The
columns IIIB and A-G in the table list the pEC.sub.50 values
against various strains IIIB, A-G.
Strain IIIB is wild type HIV-LAI strain; Strain A contains mutation
Y181C in HIV reverse transcriptase, Strain B contains mutation
K103N in HIV reverse transcriptase, Strain C contains mutation
L100I in HIV reverse transcriptase, Strain D contains mutation
Y188L and S162K in HIV reverse transcriptase, Strain E contains
mutations L100I and K103N in HIV reverse transcriptase, Strain F
contains mutations K101E and K103N in HIV reverse
transcriptase.
TABLE-US-00001 Compound number IIIB A B C D E F 1 9.24 9.20 8.85
9.20 9.22 8.97 8.98 A 8.55 8.00 8.75 8.54 8.61 8.09 8.34
[0075] Compound A is a reference compound and is the compound
referred to as `Intermediate 1` in example 1 and has been described
in WO-00/27825.
* * * * *